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CN-121971472-A - Pharmaceutical composition containing Azvudine and VEGFR-TKI inhibitor and application of pharmaceutical composition in resisting liver cancer

CN121971472ACN 121971472 ACN121971472 ACN 121971472ACN-121971472-A

Abstract

Provides a pharmaceutical composition containing an Azvudine and a VEGFR-TKI inhibitor and application thereof in resisting liver cancer, and relates to the technical field of biological medicines. In vivo and in vitro experiments prove that the alzvudine and the VEGFR-TKI have obvious synergistic effect in liver cancer treatment, and on the basis of obviously reducing the clinical dosage of the core targeting drug VEGFR-TKI, the pharmaceutical composition provided by the invention can still ensure and improve the anti-tumor curative effect, can effectively reduce the incidence rate of adverse reactions related to the core targeting drug, has good safety, has obvious advantages in improving the treatment compliance and the life quality of patients, and provides a new strategy for solving the clinical problem that the curative effect and the toxicity are difficult to be compatible in liver cancer targeting treatment.

Inventors

  • REN ZHIGANG
  • WANG HAIYU
  • LIU YIHAN

Assignees

  • 郑州大学第一附属医院

Dates

Publication Date
20260505
Application Date
20260206

Claims (8)

  1. 1. A pharmaceutical composition is characterized by comprising an active ingredient (i), an active ingredient (ii) and pharmaceutically acceptable auxiliary materials, wherein the active ingredient (i) in the pharmaceutical composition is Azvudine or pharmaceutically acceptable salt, stereoisomer or isotope derivative thereof, and the active ingredient (ii) in the pharmaceutical composition is VEGFR tyrosine kinase inhibitor or pharmaceutically acceptable salt, stereoisomer or isotope derivative thereof.
  2. 2. The pharmaceutical composition of claim 1, wherein the VEGFR tyrosine kinase inhibitor is a multi-target tyrosine kinase inhibitor with the main pharmacological action of inhibiting vascular endothelial growth factor receptor.
  3. 3. A pharmaceutical composition according to claim 2, wherein the multi-target tyrosine kinase inhibitor is a compound that simultaneously inhibits VEGFR and at least one other kinase selected from FGFR, PDGFR, c-Kit, ret, raf, MET, AXL.
  4. 4. A pharmaceutical composition according to claim 3, wherein the VEGFR tyrosine kinase inhibitor is selected from any one of, or any combination of, lenvatinib, sorafenib, regorafenib, cabotinib, sunitinib, pazopanib, acitinib, an Luoti, furquitinib, ceridinib, vandetanib, and nipanib.
  5. 5. The pharmaceutical composition of claim 4, wherein the VEGFR tyrosine kinase inhibitor is lenvatinib or a pharmaceutically acceptable salt thereof.
  6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dosage of the azloc in each unit dosage form is selected from 1mg to 20mg and the dosage of the VEGFR-TKI inhibitor in each unit dosage form is selected from 1mg to 50mg.
  7. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is formulated into any one of a capsule, a pill, a granule, an oral solution, an oral suspension and an injection, wherein the active ingredient (i) and the active ingredient (ii) are used as active ingredients and pharmaceutically acceptable auxiliary materials, and the active ingredient (i) and the active ingredient (ii) are used as independent dosage forms or are used in the same dosage form.
  8. 8. Use of a pharmaceutical composition according to any one of claims 1-7 for the preparation of a medicament for the treatment of liver cancer.

Description

Pharmaceutical composition containing Azvudine and VEGFR-TKI inhibitor and application of pharmaceutical composition in resisting liver cancer Technical Field The invention relates to the technical field of biological medicines, in particular to a pharmaceutical composition containing an Azvudine and a VEGFR-TKI inhibitor and application thereof in resisting liver cancer. Background Liver cancer is a common malignant tumor in China, the number of new cases is the fourth most serious malignant tumor, and the number of death cases is the second most serious malignant tumor. Real world studies show that 69.8% of hepatocellular carcinoma (Hepatocellular carcinoma, HCC) patients in our country are at middle and late stages of the disease at the time of the visit, and radical treatment is severely limited. Therefore, systemic drug therapy becomes a cornerstone for the treatment of advanced liver cancer. Among the many systemic therapeutic strategies, targeted therapy plays a central role. The principle is that the specific action is on the key driving signal path in the tumorigenesis and development process. In liver cancer, vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) -mediated tumor angiogenesis signaling pathways are one of the core driving mechanisms that have been demonstrated. Therefore, multi-target Tyrosine Kinase Inhibitors (TKI) using VEGFR as a main target, such as lenvatinib (Lenvatinib, also commonly known as lenvatinib, CAS number 417716-92-8, molecular formula C21H19ClN4O 4), sorafenib, dorafinib, regorafenib, and the like, can inhibit tumor neovascularization, inhibit tumor growth, regulate tumor immune microenvironment by blocking the passage, have become first-line standard therapeutic drugs, and significantly improve survival prognosis of patients. However, the clinical application of such targeted drugs still faces serious challenges. The curative effects of the traditional Chinese medicine composition are different from each other, and most patients can finally generate drug resistance. More importantly, the common adverse reactions (such as hypertension, proteinuria, skin reaction of hands and feet, hypodynamia and the like) have definite dose dependence, and the treatment is interrupted or reduced when serious, so that the full play of the curative effect is affected. Therefore, how to improve the curative effect of the existing targeted drug and reduce the toxicity related to the treatment is a key problem to be solved in clinical treatment of liver cancer. The search for new combination therapeutic strategies is an important direction to overcome drug resistance, improve efficacy and improve safety. Azvudine (Azvudine) is the first global double-target anti-AIDS innovative drug, is a broad-spectrum RNA virus inhibitor, and can selectively enter HIV-1 target cell CD4+T lymphocyte to play a role. The chemical name is 1- (4-azido-2-deoxy-2-fluoro-beta-D-ribofuranosyl) cytosine. CAS number 1011529-10-4, molecular formula C9H11FN6O4. Early studies (e.g., patent cn201010506595. X) revealed that alzvudine exhibits broad inhibitory activity against a variety of tumor cell and animal transplantation tumor models, and its mechanism of action may be related to interfering with tumor cell nucleic acid synthesis and modulating immune microenvironment. This provides a theoretical basis for combining it with existing targeted drugs and constructing a therapeutic regimen with complementary mechanisms. Currently, studies have explored combination anti-tumor regimens of alzvudine with other types of drugs, but focus on different mechanisms of action and therapeutic targets. For example, publication CN116407640a discloses a combination of alzvudine with chemotherapeutics (e.g. capecitabine, cyclophosphamide) aimed at enhancing direct cytotoxicity, publication CN116196325A explores a combination of alzvudine with immune checkpoint inhibitors (e.g. PD-1 antibodies) aimed at synergistically modulating the immune system of the body to attack tumors, publication CN116212030a relates to a combination of alzvudine with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI, such as octtinib) for the treatment of EGFR mutant non-small cell lung cancer. However, the combination of the alzvudine and a multi-target Tyrosine Kinase Inhibitor (TKI) with unique action mechanism and main anti-angiogenesis function is used for the research of treating liver cancer, and has not been reported yet. More importantly, none of the various combinations of alzvudine in the prior art have been addressed nor suggested to address the critical clinical problem of dose limiting toxicity of targeted drugs (particularly anti-angiogenic TKIs) themselves by combination. In view of the distinct action mechanisms of the two, whether the two are combined can generate a synergistic effect or not is explored, and the clinical use dosage of the multi-target TKI can be effectively reduced on the premise of ens